-
1.
Differential responses to folic acid in an established keloid fibroblast cell line are mediated by JAK1/2 and STAT3.
McCann, KJ, Yadav, M, Alishahedani, ME, Freeman, AF, Myles, IA
PloS one. 2021;(3):e0248011
Abstract
Keloids are a type of disordered scar formation which not only show heterogeneity between individuals and within the scar itself, but also share common features of hyperproliferation, abnormal extra-cellular matrix deposition and degradation, as well as altered expression of the molecular markers of wound healing. Numerous reports have established that cells from keloid scars display Warburg metabolism-a form of JAK2/STAT3-induced metabolic adaptation typical of rapidly dividing cells in which glycolysis becomes the predominant source of ATP over oxidative phosphorylation (OxPhos). Using the JAK1/2 inhibitor ruxolitinib, along with cells from patients with STAT3 loss of function (STA3 LOF; autosomal dominant hyper IgE syndrome) we examined the role of JAK/STAT signaling in the hyperproliferation and metabolic dysregulation seen in keloid fibroblasts. Although ruxolitinib inhibited hyperactivity in the scratch assay in keloid fibroblasts, it paradoxically exacerbated the hyper-glycolytic state, possibly by further limiting OxPhos via alterations in mitochondrial phosphorylated STAT3 (pSTAT3Ser727). In healthy volunteer fibroblasts, folic acid exposure recapitulated the exaggerated closure and hyper-glycolytic state of keloid fibroblasts through JAK1/2- and STAT3-dependent pathways. Although additional studies are needed before extrapolating from a representative cell line to keloids writ large, our results provide novel insights into the metabolic consequences of STAT3 dysfunction, suggest a possible role for folate metabolism in the pathogenesis of keloid scars, and offer in vitro pre-clinical data supporting considerations of clinical trials for ruxolitinib in keloid disorder.
-
2.
Effect of Mannitol plus Vitamins B in the management of patients with piriformis syndrome.
Huang, ZF, Lin, BQ, Torsha, TT, Dilshad, S, Yang, DS, Xiao, J
Journal of back and musculoskeletal rehabilitation. 2019;(2):329-337
Abstract
BACKGROUND Piriformis syndrome (PS) is an entrapment of the sciatic nerve by the piriformis muscle, or myofascial pain from the piriformis muscle. OBJECTIVE The aim of this study was to investigate the effectiveness of Mannitol plus Vitamins B regime in the management of PS. METHODS Twenty two patients were included in this study and received 250 ml of mannitol 20% intravenous infusion for 5 days + Vitamins B (vitamin B1 10 mg + vitamin B2 10 mg + vitamin B12 50 μg PO) for 6 weeks. Clinical outcomes were assessed systematically by clinical tests (tenderness, FAIR test, Beatty's, Freiberg's and Pace's maneuver), Numeric Rating Scale (NRS), Likert Analogue Scale (LAS), and MR examination. RESULTS The clinical evaluations showed a significant reduction (p< 0.05) of tenderness, FAIR test, Beatty's maneuver, Freiberg's maneuver and Pace's maneuver when compared with baseline evaluation during the 3rd and 6th month follow-ups. A statistically significant improvement of pain was measured by NRS at resting (p< 0.001), at night (p< 0.001) and during activities (p< 0.001) and LAS with prolonged sitting (p< 0.001), standing (p< 0.001) and lying (p< 0.001). Concomitantly, swelling of SN revealed a significant reduction (p= 0.003) from 86.4% to 18.2%. CONCLUSIONS Mannitol plus Vitamins B is effective in the management of piriformis syndrome and it could be an alternative regime in treating PS.
-
3.
One-year follow-up of B vitamin and Iron status in patients with phenylketonuria provided tetrahydrobiopterin (BH4).
Brantley, KD, Douglas, TD, Singh, RH
Orphanet journal of rare diseases. 2018;(1):192
Abstract
BACKGROUND People with Phenylketonuria (PKU) who respond to tetrahydrobiopterin (BH4) often decrease dependence on medical food (MF) following increased phenylalanine (phe) tolerance. Responders to BH4 may experience a reduction in certain nutrients if not compensated through intact foods or supplements. This study investigated B6, B12, folate, and iron status based on blood levels and dietary intake in patients with PKU responsive to BH4 over 1 year. METHODS Fifty-eight patients with PKU, ages 4-50 years were recruited and initiated on BH4 therapy. Patients were monitored for BH4 response, and nutritional status was recorded at regular intervals over 12 months. The analysis included 33 patients with known BH4 response status and complete nutritional data. Nutrient intake was determined by National Data System for Research (NDSR) analysis of self reported 3 day diet records and compared to Dietary Reference Intakes (DRIs). Blood biomarkers were analyzed by Quest Diagnostics and compared to laboratory reference ranges. Patient laboratory values were compared to controls from the National Health and Examination Survey (NHANES). Differences in nutrient intakes across time points were examined, stratified by age, using nonparametric methods. Statistical analyses were completed with SAS 9.4, with significance set at α = 0.05. RESULTS Medical food intake declined among pediatric (p < 0.01) and adult (p = 0.06) BH4 responders over 1 year. Among those < 18 years of age, mean percent of calories obtained from MF declined from 21.3 to 4.7%. In adults, percent calories from MF dropped from 19.5 to 4.0%. Though maintaining laboratory and dietary values within reference ranges, responders < 18 years experienced a significant decline in serum B12 (p = 0.01), dietary folate (p = 0.006), and dietary iron (p = 0.004) over the study. CONCLUSION Although mean dietary and laboratory values for B12, B6, folate, and iron in BH4 responders and non-responders were adequate at baseline and 12-month follow-up, responders experienced a significant decline in serum B12 over 1 year, which may be explained by decreased intake of fortified MF. Both response groups had lower serum B12 than NHANES controls at baseline and 12 months. Results indicate a need to monitor B12 concentrations and consider micronutrient supplementation, with special attention to pediatric patients with PKU.
-
4.
Pretreatment Red Blood Cell Total Folate Concentration Is Associated With Response to Pemetrexed in Stage IV Nonsquamous Non-Small-cell Lung Cancer.
Bagley, SJ, Vitale, S, Zhang, S, Aggarwal, C, Evans, TL, Alley, EW, Cohen, RB, Langer, CJ, Blair, IA, Vachani, A, et al
Clinical lung cancer. 2017;(2):e143-e149
-
-
Free full text
-
Abstract
INTRODUCTION Pemetrexed inhibits folate-dependent enzymes involved in pyrimidine and purine synthesis. Previous studies of genetic variation in these enzymes as predictors of pemetrexed efficacy have yielded inconsistent results. We investigated whether red blood cell (RBC) total folate, a phenotypic rather than genotypic, marker of cellular folate status was associated with the response to pemetrexed-based chemotherapy in advanced nonsquamous non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS We conducted a prospective cohort study of patients with stage IV nonsquamous NSCLC receiving first-line chemotherapy containing pemetrexed. The pretreatment RBC total folate level was quantified using liquid chromatography mass spectrometry. We then compared the objective response rate (ORR) between patients with RBC total folate concentrations greater than and less than an optimal cutoff value determined from the receiver operating characteristic curve. A logistic regression model was used to adjust for age, sex, and the use of bevacizumab. RESULTS The ORR was 62% (32 of 52 patients). Receiver operating characteristic analysis was used to establish that a RBC total folate cutoff value of 364.6 nM optimally discriminated between pemetrexed responders and nonresponders. Patients with RBC total folate < 364.5 nM had an ORR of 27% compared with 71% for patients with RBC total folate > 364.5 nM (P = .01). This difference persisted after adjusting for age, sex, and the use of bevacizumab (odds ratio, 0.07; 95% confidence interval, 0.01-0.57; P = .01). CONCLUSION A low pretreatment RBC total folate was associated with an inferior response to pemetrexed-based chemotherapy in stage IV nonsquamous NSCLC. Larger, multicenter studies are needed to validate RBC total folate as a predictive marker of pemetrexed response.
-
5.
Effect of niacin on triglyceride-rich lipoprotein apolipoprotein B-48 kinetics in statin-treated patients with type 2 diabetes.
Pang, J, Chan, DC, Hamilton, SJ, Tenneti, VS, Watts, GF, Barrett, PH
Diabetes, obesity & metabolism. 2016;(4):384-91
-
-
Free full text
-
Abstract
AIM: To investigate the effects of extended-release (ER) niacin on apolipoprotein B-48 (apoB-48) kinetics in statin-treated patients with type 2 diabetes (T2DM). METHODS A total of 12 men with T2DM were randomized to rosuvastatin or rosuvastatin plus ER niacin for 12 weeks and then crossed to the alternate therapy. Postprandial metabolic studies were performed at the end of each treatment period. D3-leucine tracer was administered as subjects consumed a high-fat liquid meal. ApoB-48 kinetics were determined using stable isotope tracer kinetics with fractional catabolic rates (FCRs) and secretion rates derived using a non-steady-state compartmental model. Area-under-the-curve (AUC) and incremental AUC (iAUC) for plasma triglyceride and apoB-48 were also calculated over the 10-h period after ingestion of the fat meal. RESULTS In statin-treated patients with T2DM, apoB-48 concentration was lower with ER niacin (8.24 ± 1.98 vs 5.48 ± 1.14 mg/l, p = 0.03) compared with statin alone. Postprandial triglyceride and apoB-48 AUC were also significantly lower on ER niacin treatment (-15 and -26%, respectively; p < 0.05), without any change to triglyceride and apoB-48 iAUC. ApoB-48 secretion rate in the basal state (3.21 ± 0.34 vs 2.50 ± 0.31 mg/kg/day; p = 0.04) and number of apoB-48-containing particles secreted in response to the fat load (1.35 ± 0.19 vs 0.84 ± 0.12 mg/kg; p = 0.02) were lower on ER niacin. ApoB-48 FCR was not altered with ER niacin (8.78 ± 1.04 vs 9.17 ± 1.26 pools/day; p = 0.79). CONCLUSIONS ER niacin reduces apoB-48 concentration by lowering fasting and postprandial apoB-48 secretion rate. This effect may be beneficial for lowering atherogenic postprandial lipoproteins and may provide cardiovascular disease risk benefit in patients with T2DM.
-
6.
Lowered Levels of Carbonyl Proteins after Vitamin B Supplementation in Patients with Mild Cognitive Impairment and Alzheimer's Disease.
Rommer, PS, Fuchs, D, Leblhuber, F, Schroth, R, Greilberger, M, Tafeit, E, Greilberger, J
Neuro-degenerative diseases. 2016;(3-4):284-9
Abstract
BACKGROUND The critical role of neuro-inflammation and oxidative stress in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD) has become evident. OBJECTIVE The aim of this study is to assess the influence of vitamin supplementation on parameters of oxidative stress, inflammation as well as on cognition in patients with AD and mild cognitive impairment. METHODS In our study, patients with cognitive impairment and healthy controls were enrolled. All patients were intended to receive vitamin supplementation (vitamin B1, B6, B12 and folic acid) for 3 months. Mini Mental State Examination (MMSE) and laboratory markers [carbonyl proteins (CPs), malondialdehyde, tryptophan (Trp), kynurenine (Kyn), neopterin, folic acid, vitamin B12 level] were assessed for patients and controls at baseline and after 3 months. After half of the patients had been treated for 3 months, analyses were performed resulting in 3 subgroups: healthy controls without supplementation (15 subjects, 11 females), patients with vitamin supplementation (17 subjects, 10 females) and patients without vitamin supplementation (16 subjects, 9 females; baseline values prior to supplementation). RESULTS Age was significantly higher for the supplemented group (76.4 ± 6.7 years) compared to vitamin-naïve patients (63.3 ± 13.7 years; p < 0.01). The MMSE score was higher in the supplemented group (23.1 ± 4.8 vs. 20.3 ± 9.5) but did not reach significance. Levels of CPs were significantly higher in the vitamin-naïve patients (p < 0.05). Levels of Kyn and the Kyn/Trp ratio were significantly lower in vitamin-naïve patients compared to the supplemented group (p < 0.05). No significant difference was seen for the other markers. CONCLUSION Vitamin supplementation leads to reduced levels of CPs in patients. Pearson's correlation coefficient shows a negative relation (r = -0.69) between CPs and MMSE. Future trials should assess whether CPs might be suitable markers for monitoring of demented patients.
-
7.
Hyperhomocysteinaemia and chronic venous ulcers.
de Franciscis, S, De Sarro, G, Longo, P, Buffone, G, Molinari, V, Stillitano, DM, Gallelli, L, Serra, R
International wound journal. 2015;(1):22-6
-
-
Free full text
-
Abstract
Chronic venous ulceration (CVU) is the major cause of chronic wounds of lower extremities, and is a part of the complex of chronic venous disease. Previous studies have hypothesised that several thrombophilic factors, such as hyperhomocysteinaemia (HHcy), may be associated with chronic venous ulcers. In this study, we evaluated the prevalence of HHcy in patients with venous leg ulcers and the effect of folic acid therapy on wound healing. Eighty-seven patients with venous leg ulcers were enrolled in this study to calculate the prevalence of HHcy in this population. All patients underwent basic treatment for venous ulcer (compression therapy ± surgical procedures). Patients with HHcy (group A) received basic treatment and administered folic acid (1·2 mg/day for 12 months) and patients without HHcy (group B) received only basic treatment. Healing was assessed by means of computerised planimetry analysis. The prevalence of HHcy among patients with chronic venous ulcer enrolled in this study was 62·06%. Healing rate was significantly higher (P < 0·05) in group A patients (78·75%) compared with group B patients (63·33%). This study suggests a close association, statistically significant, between HHcy and CVU. Homocysteine-lowering therapy with folic acid seems to expedite wound healing. Despite these aspects, the exact molecular mechanisms between homocysteine and CVU have not been clearly defined and further studies are needed.
-
8.
Effect of Extended-Release Niacin/Laropiprant Combination on Plasma Adiponectin and Insulin Resistance in Chinese Patients with Dyslipidaemia.
Hu, M, Yang, YL, Masuda, D, Yamashita, S, Tomlinson, B
Disease markers. 2015;:154014
Abstract
OBJECTIVES This study examined whether the increase of adiponectin associated with extended-release (ER) niacin/laropiprant combination attenuates the adverse effect of niacin on glucose and insulin resistance in Hong Kong Chinese patients with dyslipidaemia. METHODS Patients (N = 121) were treated with ER niacin/laropiprant 1 g/20 mg for 4 weeks and then the dose was doubled for an additional 8 weeks. Measurements of fasting lipids, glucose, insulin, and adiponectin were performed at baseline and during the study. RESULTS There were significant (P < 0.001) increases in glucose (9.4 ± 13.1%), insulin (70.2 ± 91.0%), HOMA-IR (87.8 ± 103.9%), and adiponectin (169.3 ± 111.6%). The increase in adiponectin was significantly associated with increase in glucose (r = 0.221, P < 0.05), insulin (r = 0.184, P < 0.05), and HOMA-IR (r = 0.237, P < 0.01) and the association remained significant after adjustment for changes in body weight or body fat mass. CONCLUSION Treatment with ER niacin/laropiprant led to a significant increase in adiponectin levels but worsening of glucose levels and insulin resistance, and the increase in adiponectin and insulin resistance were correlated suggesting the increase in adiponectin did not ameliorate the deterioration in insulin resistance. Clinical trial is registered with number on WHO-ICTRP ChiCTR-ONC-10001038.
-
9.
Phase I clinical trial of 99mTc-etarfolatide, an imaging agent for folate receptor in healthy Japanese adults.
Yamada, Y, Nakatani, H, Yanaihara, H, Omote, M
Annals of nuclear medicine. 2015;(9):792-8
Abstract
OBJECTIVE Technetium etarfolatide ((99m)Tc-EF) is a radioactive diagnostic imaging agent that was developed to assess the expression of folate receptors in tumors. Administering folic acid prior to the administration of (99m)Tc-EF has been shown to improve SPECT images. Here, we conducted a phase I clinical trial to assess the safety, pharmacokinetics, and radiation dosimetry of (99m)Tc-EF injection following pre-administration of folic acid in healthy Japanese male adults. METHODS Six healthy Japanese male adults were enrolled in the study. Folic acid was intravenously administered, followed 1-3 min later by an intravenous injection of (99m)Tc-EF (740 MBq ± 20 %). Assessments of subjective symptoms and objective findings, electrocardiograms, physical examination, and laboratory tests were performed before and up to 7 days after the injection to assess the safety of (99m)Tc-EF. Blood and urine collections and whole-body planar imaging were conducted at various time points up to 24 h after the injection to assess the pharmacokinetics of (99m)Tc-EF. The internal radiation dosimetry was calculated based on the pharmacokinetics results using the MIRD method. RESULTS Five adverse events were observed in three subjects (50 %) after administration of the folic acid and (99m)Tc-EF, while these events were mild and non-serious. Of those five events, three were considered to be related to the administered agents. The radioactivity in blood rapidly decreased and showed a biphasic profile. The activity of (99m)Tc-EF at 5 min post injection was largest in the bone marrow, followed by the liver and kidneys, and had decreased within 24 h in all organs/tissues without appreciable retention. The pharmacokinetics results suggested that (99m)Tc-EF was mainly eliminated by kidney. The results also suggested that when administered at 925 MBq of (99m)Tc-EF, which is the maximum dose generally used for clinical trials in other countries, the corresponding effective dose of (99m)Tc-EF is equal to or less than those determined for the current radioactive diagnostic imaging agents. CONCLUSIONS The results of this study assessing the safety and radiation dosimetry of (99m)Tc-EF with folic acid pre-administration suggested that folic acid and (99m)Tc-EF should be appropriate for further studies. No pharmacokinetics concerns were noted.
-
10.
A phase II study of pralatrexate with vitamin B12 and folic acid supplementation for previously treated recurrent and/or metastatic head and neck squamous cell cancer.
Ho, AL, Lipson, BL, Sherman, EJ, Xiao, H, Fury, MG, Apollo, A, Seetharamu, N, Sima, CS, Haque, S, Lyo, JK, et al
Investigational new drugs. 2014;(3):549-54
Abstract
BACKGROUND Pralatrexate (Fotolyn(TM); Allos Therapeutics Inc.) is an antifolate dihydrofolate reductase (DHFR) inhibitor. We conducted a phase II study of pralatrexate with folic acid and B12 supplementation in patients with recurrent and/or metastatic head and neck squamous cell cancer (R/M HNSCC). PATIENTS AND METHODS This was a single-arm, Simon optimal two stage phase II study. Patients with R/M HNSCC previously treated with chemotherapy were eligible. The study was initiated with a dosing schedule of pralatrexate 190 mg/m(2) biweekly on a 4-week cycle with vitamin supplementation. Due to toxicity concerns, the dosing was modified to 30 mg/m(2) weekly for 3 weeks in a 4-week cycle with vitamin supplementation. Radiologic imaging was to be obtained about every 2 cycles. RESULTS Thirteen subjects were enrolled; 12 were treated. Seven of the twelve patients had previously received ≥2 lines of chemotherapy. The most common grade 3 toxicity was mucositis (3 patients). Seven patients did not complete two cycles of therapy due to progression of disease (4), toxicity (1), death (1), and withdrawal of consent (1). Two deaths occurred: one due to disease progression and the other was an unwitnessed event that was possibly related to pralatrexate. No clinical activity was observed. The median overall survival was 3.1 months. The study was closed early due to lack of efficacy. CONCLUSIONS Pralatrexate does not possess clinical activity against previously treated R/M HNSCC. Evaluation of pralatrexate in other clinical settings of HNSCC management with special considerations for drug toxicity may be warranted.